FREE BASE CRYSTALLINE FORM OF A COMPLEMENT COMPONENT C5a RECEPTOR

ABSTRACT

Provided herein is a free base crystalline form of a complement component 5a receptor having the formula of Compound 1 
     
       
         
         
             
             
         
       
     
     Also provided herein are pharmaceutical compositions and methods of treatment using the crystalline free base form of Compound 1 described herein.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/307,865 filed May 4, 2021, which is a divisional of U.S. patentapplication Ser. No. 17/091,019 filed Nov. 6, 2020, which applicationclaims the benefit of priority under 35 U.S.C § 119(e) to U.S.Provisional Application Ser. No. 62/932,652 filed Nov. 8, 2019, thedisclosures of each are incorporated herein by reference in theirentirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

NOT APPLICABLE

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

NOT APPLICABLE

BACKGROUND OF THE INVENTION

The complement system plays a central role in the clearance of immunecomplexes and in immune responses to infectious agents, foreignantigens, virus infected cells and tumor cells. Inappropriate orexcessive activation of the complement system can lead to harmful, andeven potentially life-threatening consequences due to severeinflammation and resulting tissue destruction. These consequences areclinically manifested in various disorders including septic shock;myocardial, as well as, intestinal ischemia/reperfusion injury; graftrejection; organ failure; nephritis; pathological inflammation; andautoimmune diseases.

The complement system is composed of a group of proteins that arenormally present in the serum in an inactive state. Activation of thecomplement system encompasses mainly three distinct pathways, i.e., theclassical, the alternative, and the lectin pathway (V. M. Holers, InClinical Immunology: Principles and Practice, ed. R. R. Rich, MosbyPress; 1996, 363-391): 1) The classical pathway is acalcium/magnesium-dependent cascade, which is normally activated by theformation of antigen-antibody complexes. It can also be activated in anantibody-independent manner by the binding of C-reactive protein,complexed with ligand, and by many pathogens including gram-negativebacteria. 2) The alternative pathway is a magnesium-dependent cascadewhich is activated by deposition and activation of C3 on certainsusceptible surfaces (e.g. cell wall polysaccharides of yeast andbacteria, and certain biopolymer materials). 3) The lectin pathwayinvolves the initial binding of mannose-binding lectin and thesubsequent activation of C2 and C4, which are common to the classicalpathway (Matsushita, M. et al., J. Exp. Med. 176: 1497-1502 (1992);Suankratay, C. et al., J. Immunol. 160: 3006-3013 (1998)).

The activation of the complement pathway generates biologically activefragments of complement proteins, e.g. C3a, C4a and C5a anaphylatoxinsand C5b-9 membrane attack complexes (MAC), all which mediateinflammatory responses by affecting leukocyte chemotaxis; activatingmacrophages, neutrophils, platelets, mast cells and endothelial cells;and increasing vascular permeability, cytolysis and tissue injury.

Complement C5a is one of the most potent proinflammatory mediators ofthe complement system. (The anaphylactic C5a peptide is 100 times morepotent, on a molar basis, in eliciting inflammatory responses than C3a.)C5a is the activated form of C5 (190 kD, molecular weight). C5a ispresent in human serum at approximately 80 μg/ml (Kohler, P. F. et al.,J. Immunol. 99: 1211-1216 (1967)). It is composed of two polypeptidechains, α and β, with approximate molecular weights of 115 kD and 75 kD,respectively (Tack, B. F. et al., Biochemistry 18: 1490-1497 (1979)).Biosynthesized as a single-chain promolecule, C5 is enzymaticallycleaved into a two-chain structure during processing and secretion.After cleavage, the two chains are held together by at least onedisulfide bond as well as noncovalent interactions (Ooi, Y. M. et al.,J. Immunol. 124: 2494-2498(1980)).

Recent work has identified(2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide,Compound 1

as useful for treating C5a mediated diseases. Despite thisidentification, the efficient delivery of biologically relevant amountsof Compound 1 remains challenging.

As such, there is a need to identify solid forms of Compound 1 that canimprove important biological characteristics such as solubility,dissolution rate, and bioavailability, without sacrificing stability andpotency. The present disclosure addresses these needs and providesrelated advantages as well.

BRIEF SUMMARY OF THE INVENTION

Provided herein is a free base crystalline form of Compound 1, methodsof using the same, and pharmaceutical compositions prepared using a freebase crystalline form of Compound 1.

In some aspects, provided herein is a free base crystalline form of(2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide,Compound 1

The free base crystalline form of Compound 1 can be characterized usingvarious techniques including, but not limited to, X-ray powderdiffraction (XRPD) and differential scanning calorimetry (DSC). Relevantcharacterizing features from the listed techniques are further describedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of the freebase crystalline form described in Example 1.

FIG. 2 shows the differential scanning calorimetry (DSC) thermogram ofthe free base crystalline form of Compound 1.

DETAILED DESCRIPTION OF THE INVENTION I. General

The present disclosure provides a free base crystalline form ofCompound 1. This form is suitable for preparing pharmaceuticalcompositions including oral solid dosage forms such as tablet, capsule,softgel, oral liquid dosage forms such as solutions and suspensions,topical dosage forms such as semisolids, ointments, pastes, creams andgels, inhalation dosage forms, and parenteral dosage forms such as IV,IM and SC; but not limited to the above-mentioned dosage forms.

II. Definitions

The terms “about” and “around,” as used herein to modify a numericalvalue, indicate a close range around that explicit value. If “X” werethe value, “about X” or “around X” would indicate a value from 0.9X to1.1X, and more preferably, a value from 0.95X to 1.05X. Any reference to“about X” or “around X” specifically indicates at least the values X,0.95X, 0.96X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus,“about X” and “around X” are intended to teach and provide writtendescription support for a claim limitation of, e.g., “0.98X.”

“Compound 1” is a chemical compound having an IUPAC name of(2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide,and the structure shown below:

“Substantially free” refers to an amount of 10% or less of another form,preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, or less of another form.

The term “treating” or “treatment” encompasses both disease-modifyingtreatment and symptomatic treatment, either of which may be prophylactic(i.e., before the onset of symptoms, in order to prevent, delay orreduce the severity of symptoms) or therapeutic (i.e., after the onsetof symptoms, in order to reduce the severity and/or duration ofsymptoms).

As used herein, a condition is considered “responsive to C5a receptormodulation” if modulation of C5a receptor activity results in thereduction of inappropriate activity of a C5a receptor.

The term “individual” refers to mammals, which includes primates(especially humans), domesticated companion animals (such as dogs, cats,horses, and the like) and livestock (such as cattle, pigs, sheep, andthe like), with dosages as described herein. In some embodiments, theterm “individual” refers to a human.

III. Detailed Description of Embodiments

A. Free Base Crystalline Form of Compound 1

In some aspects, provided herein is a free base crystalline formCompound 1

which is substantially free of other forms of Compound 1.

In some embodiments, the free base crystalline form of Compound 1 ischaracterized by an X-ray powder diffraction pattern comprising peaks at8.1, 8.4, 14.1, 16.9, and 19.0 degrees 2θ (±0.2 degrees 2θ). In someembodiments, the free base crystalline form of Compound 1 is furthercharacterized by an X-ray powder diffraction pattern comprising peaks at12.4, 15.2, 16.1, 24.4, and 24.7 degrees 2θ (±0.2 degrees 2θ). In someembodiments, the free base crystalline form of Compound 1 ischaracterized by an X-ray powder diffraction pattern substantially inaccordance with FIG. 2 .

Differential scanning calorimetry (DSC) can also be used to characterizethe free base crystalline form of Compound 1. In some embodiments, thefree base crystalline form of Compound 1 is characterized by adifferential scanning calorimetry thermogram (DSC) comprising anendothermic peak at around 216° C. In some embodiments, the free basecrystalline form of Compound 1 is characterized by a melting point onsetof about 213° C. as determined by differential scanning calorimetrythermogram (DSC). In some embodiments, the free base crystalline form ofCompound 1 is characterized by a differential scanning calorimetry (DSC)thermogram substantially in accordance with FIG. 2 .

B. Methods of Making a Free Base Crystalline Form of Compound 1

Compound 1 can be prepared as described previously. See, for example,WO2010/075257, the contents of each are incorporated by reference intheir entirety for all purposes.

The free base crystalline form described herein can be prepared asdescribed in the provided Examples. It is understood that there may bemore than one crystallization method that will yield the described freebase crystalline form.

C. Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising a free basecrystalline form of Compound 1 or liquid pharmaceutical compositionsprepared using the free base crystalline form of Compound 1.Pharmaceutical compositions will include one or more pharmaceuticallyacceptable excipients.

The pharmaceutical compositions containing the free base crystallineform of Compound 1 may be in a form suitable for oral use, for example,as tablets, troches, lozenges, liquid formulations, aqueous or oilysuspensions, dispersible powders or granules, emulsions and selfemulsifications as described in U.S. Patent Application 2002-0012680,hard or soft capsules, syrups, elixirs, solutions, buccal patch, oralgel, chewing gum, chewable tablets, effervescent powder and effervescenttablets. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, antioxidants and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the free base crystalline form of Compound 1 in admixture withnon-toxic pharmaceutically acceptable excipients which are suitable forthe manufacture of tablets. These excipients may be for example, inertdiluents, such as cellulose, silicon dioxide, aluminum oxide, calciumcarbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example, corn starch, or alginic acid; binding agents, forexample PVP, cellulose, PEG, starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated, enterically or otherwise,by known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and U.S. Pat. No. 4,265,874 to form osmotic therapeutictablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the free base crystalline form of Compound 1 is mixed with aninert solid diluent, for example, calcium carbonate, calcium phosphateor kaolin, or as soft gelatin capsules wherein the free base crystallineform of Compound 1 is mixed with water or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil. Additionally, emulsions canbe prepared with a non-water miscible ingredient such as oils andstabilized with surfactants such as mono-diglycerides, PEG esters andthe like.

Aqueous suspensions for oral use contain the free base crystalline formof Compound 1 in admixture with excipients suitable for the manufactureof aqueous suspensions. Such excipients are suspending agents, forexample sodium carboxymethylcellulose, methylcellulose,hydroxy-propylmethylcellulose, hydroxy-propylcellulose, sodium alginate,polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents may be a naturally-occurring phosphatide, for examplelecithin, or condensation products of an alkylene oxide with fattyacids, for example polyoxy-ethylene stearate, or condensation productsof ethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate as well asother poloxamers (e.g. Poloxamer F-68). The aqueous suspensions may alsocontain one or more preservatives, for example ethyl, or n-propyl,p-hydroxybenzoate, one or more coloring agents, one or more flavoringagents, and one or more sweetening agents, such as sucrose or saccharin.

Accordingly, provided herein is aqueous suspension comprising the freebase crystalline form of Compound 1 and at least one excipient. In someembodiments, the at least one excipient is at least one suspending agentand/or at least one wetting agent as described above.

Oily suspensions for oral use may be formulated by suspending the freebase crystalline form of Compound 1 in a vegetable oil, for examplearachis oil, olive oil, sesame oil or coconut oil, or in a mineral oilsuch as liquid paraffin. The oily suspensions may contain a thickeningagent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteningagents such as those set forth above, and flavoring agents may be addedto provide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions may be in the form of a sterileinjectable or infusable aqueous or oleagenous solution or suspension.This solution or suspension may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butane diol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution, isotonic sodium chloridesolution, isotonic aqueous buffer solutions, as well as mixtures ofsaline, a disintegrating agent such as PEG (e.g. PEG 200, PEG 400, PEG800, etc), and nonionic surfactants such as Tween80. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables and infusables.Compositions for injectable or infusable administration optionallyinclude a local anesthetic such as lignocaine to ease pain at the siteof the injection. Ingredients can be supplied pre-mixed or suppliedseparately, with mixing of the ingredients occurring shortly before use.In some embodiments, mixing shortly before use is desirable to takeadvantage of the high initial solubility of the free base crystallineform of Compound 1 in certain liquid formulation mixtures.

Injectable or infusible compositions includes, but is not limited to,intravenous administration, intramuscular administration as well assubcutaneous or intrasternal injection. Accordingly, in someembodiments, provided herein is an injectable or infusible solutioncomprising Compound 1 and at least one wetting agent or solvent, whereinthe intravenous pharmaceutical composition is prepared using the freebase crystalline form of Compound 1 described herein. In someembodiments, the injectable or infusible solution is prepared forintravenous administration. In some embodiments, the injectable orinfusible solution is prepared for intramuscular administration. In someembodiments, the injectable or infusible solution is prepared forsubcutaneous injection. In some embodiments, the injectable or infusiblesolution is prepared for intrasternal injection. In some embodiments,the at least one wetting agent or solvent in the injectable or infusiblepharmaceutical composition includes saline, a disintegrating agent, andnonionic surfactant.

Injectable or infusible compositions can be prepared at any time that isconvenient for the medical practitioner or user; this includes shortlybefore use or well in advance of use. In some embodiments, thecomposition is prepared shortly before use. Shortly before use includes0-24 hours before use, 0-10 hours before use, 0-5 hours before use, or0-1 hours before use. In some embodiments, the injectable or infusiblecomposition is prepared 0-5 hours before use. Well in advance typicallyrefers to one or more days before use. Accordingly, also provided hereinare methods of preparing injectable or infusible solution. The methodincluding, dissolving the free base crystalline form of Compound 1 withthe at least one wetting agent or solvent to prepare an injectable orinfusible solution; and administering the injectable or infusiblesolution to a subject in need thereof.

Dispersible powders and granules suitable for preparation of an aqueousoral formulations or oral suspensions by the addition of water providethe free base crystalline form of Compound 1 in admixture with adispersing or wetting agent, suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example sweetening, flavoring and coloring agents, mayalso be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the free base crystalline form ofCompound 1 with a suitable non-irritating excipient which is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials includecocoa butter and polyethylene glycols. Additionally, the compounds canbe administered via ocular delivery by means of solutions or ointments.Still further, transdermal delivery of the subject compounds can beaccomplished by means of iontophoretic patches and the like. For topicaluse, creams, ointments, jellies, solutions or suspensions, etc.,containing the compounds of the present invention are employed. As usedherein, topical application is also meant to include the use of mouthwashes and gargles.

The compounds of this invention may also be coupled a carrier that is asuitable polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of theinvention may be coupled to a carrier that is a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like. In one embodiment ofthe invention, the compound of the invention is coupled to a polymer orsemipermeable polymer matrix that is formed as a stent or stent-graftdevice.

D. Methods of Treatment

Also provided herein are methods of treating individuals suffering fromconditions that are responsive to C5a receptor modulation.

In some aspects provided herein are methods of treating an individualsuffering from or susceptible to a disease or disorder involvingpathologic activation of C5a receptors, comprising administering to theindividual an effective amount of a free base crystalline form ofCompound 1 or a pharmaceutical formulation including Compound 1 asdescribed herein.

In some embodiments, the free base crystalline form of Compound 1described herein is used for treating patients suffering from conditionsthat are responsive to C5a receptor modulation.

Conditions that can be Treated by C5a Modulation:

Autoimmune disorders—e.g., Rheumatoid arthritis, systemic lupuserythematosus, Guillain-Barre syndrome, pancreatitis, C3 glomerulopathy(C3G), hidradenitis suppurativa (HS), lupus nephritis, lupusglomerulonephritis, immunoglobulin A (IgA) nephropathy, psoriasis,Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis,multiple sclerosis, bronchial asthma, pemphigus, pemphigoid,scleroderma, myasthenia gravis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome (and associatedglomerulonephritis and pulmonary hemorrhage), immunovasculitis, tissuegraft rejection, hyperacute rejection of transplanted organs; and thelike.

Inflammatory disorders and related conditions—e.g., Neutropenia, sepsis,septic shock, Alzheimer's disease, multiple sclerosis, stroke,inflammatory bowel disease (IBD), age-related macular degeneration (AMD,both wet and dry forms), inflammation associated with severe burns, lunginjury, and ischemia-reperfusion injury, osteoarthritis, as well asacute (adult) respiratory distress syndrome (ARDS), chronic pulmonaryobstructive disorder (COPD), systemic inflammatory response syndrome(SIRS), atopic dermatitis, psoriasis, chronic urticaria and multipleorgan dysfunction syndrome (MODS). Also included are pathologicsequellae associated with insulin-dependent diabetes mellitus (includingdiabetic retinopathy), lupus nephropathy, Heyman nephritis, membranousnephritis and other forms of glomerulonephritis, contact sensitivityresponses, and inflammation resulting from contact of blood withartificial surfaces that can cause complement activation, as occurs, forexample, during extracorporeal circulation of blood (e.g., duringhemodialysis or via a heart-lung machine, for example, in associationwith vascular surgery such as coronary artery bypass grafting or heartvalve replacement), or in association with contact with other artificialvessel or container surfaces (e.g., ventricular assist devices,artificial heart machines, transfusion tubing, blood storage bags,plasmapheresis, plateletpheresis, and the like). Also included arediseases related to ischemia/reperfusion injury, such as those resultingfrom transplants, including solid organ transplant, and syndromes suchas ischemic reperfusion injury, ischemic colitis and cardiac ischemia.The free base crystalline form of Compound 1 described herein may alsobe useful in the treatment of age-related macular degeneration (Hagemanet al, P.N.A.S. 102: 7227-7232, 2005).

Cardiovascular and Cerebrovascular Disorders—e.g., myocardialinfarction, coronary thrombosis, vascular occlusion, post-surgicalvascular reocclusion, atherosclerosis, traumatic central nervous systeminjury, and ischemic heart disease. In one embodiment, an effectiveamount of a free base crystalline form of Compound 1 described hereinmay be administered to a patient at risk for myocardial infarction orthrombosis (i.e., a patient who has one or more recognized risk factorfor myocardial infarction or thrombosis, such as, but not limited to,obesity, smoking, high blood pressure, hypercholesterolemia, previous orgenetic history of myocardial infarction or thrombosis) in order reducethe risk of myocardial infarction or thrombosis.

Diseases of Vasculitis—Vasculitic diseases are characterized byinflammation of the vessels. Infiltration of leukocytes leads todestruction of the vessel walls, and the complement pathway is believedto play a major role in initiating leukocyte migration as well as theresultant damage manifested at the site of inflammation (Vasculitis,Second Edition, Edited by Ball and Bridges, Oxford University Press, pp47-53, 2008). The free base crystalline form of Compound 1 describedherein can be used to treat vasculitis, including anti-neutrophilcytoplasmic antibody associate vasculitis (or ANCA-associatedvasculitis, which includes microscopic polyangiitis, eosinophilicgranulomatosis with polyangitis, and granulomatosis with polyangiitis,which is also known as Wegener's disease), Churg-Strauss syndrome,Henoch-Schonlein purpura, polyateritis nodosa, Rapidly ProgressiveGlomerulonephritis (RPGN), cryoglobulinaemia, giant cell arteritis(GCA), Behcet's disease and Takayasu's arteritis (TAK).

HIV infection and AIDS—the free base crystalline form of Compound 1described herein may be used to inhibit HIV infection, delay AIDSprogression or decrease the severity of symptoms or HIV infection andAIDS.

Neurodegenerative disorders and related diseases—Within furtherembodiments, the free base crystalline form of Compound 1 describedherein may be used to treat Alzheimer's disease, multiple sclerosis, andcognitive function decline associated with cardiopulmonary bypasssurgery and related procedures.

Cancers—The free base crystalline form of Compound 1 described hereinare also useful for the treatment of cancers and precancerous conditionsin a subject. Specific cancers that can be treated include, but are notlimited to, sarcomas, carcinomas, and mixed tumors. Exemplary conditionsthat may be treated according to the present invention includefibrosarcomas, liposarcomas, chondrosarcomas, osteogenic sarcomas,angiosarcomas, lymphangiosarcomas, synoviomas, mesotheliomas,meningiomas, leukemias, lymphomas, leiomyosarcomas, rhabdomyosarcomas,squamous cell carcinomas, basal cell carcinomas, adenocarcinomas,papillary carcinomas, cystadenocarcinomas, bronchogenic carcinomas,melanomas, renal cell carcinomas, hepatocellular carcinomas,transitional cell carcinomas, choriocarcinomas, seminomas, embryonalcarcinomas, wilm's tumors, pleomorphic adenomas, liver cell papillomas,renal tubular adenomas, cystadenomas, papillomas, adenomas, leiomyomas,rhabdomyomas, hemangiomas, lymphangiomas, osteomas, chondromas, lipomasand fibromas.

In some embodiments, the free base crystalline form of Compound 1described herein can be used for the treatment of diseases selected fromthe group consisting of sepsis (and associated disorders), COPD,rheumatoid arthritis, lupus nephritis and multiple sclerosis.

In some embodiments, the free base crystalline form of Compound 1described herein can be used for the treatment of diseases selected fromthe group consisting of anti-neutrophil cytoplasmic antibody associate(ANCA) vasculitis, C3 glomerulopathy, hidradenitis suppurativa, andlupus nephritis.

Treatment methods provided herein include, in general, administration toa patient an effective amount of a free base crystalline form ofCompound 1. Suitable patients include those patients suffering from orsusceptible to (i.e., prophylactic treatment) a disorder or diseaseidentified herein. Typical patients for treatment as described hereininclude mammals, particularly primates, especially humans. Othersuitable patients include domesticated companion animals such as a dog,cat, horse, and the like, or a livestock animal such as cattle, pig,sheep and the like.

In general, treatment methods provided herein comprise administering toa patient an effective amount of the free base crystalline form ofCompound 1 described herein. The exact formulation, route ofadministration and dosage for the pharmaceutical compositions of thepresent invention can be chosen by the individual physician in view ofthe patient's condition. (See e.g., Fingl et al. 1975, in “ThePharmacological Basis of Therapeutics”, which is hereby incorporatedherein by reference in its entirety, with particular reference to Ch. 1,p. 1). In some embodiments, the free base crystalline form of Compound 1described herein is administered to a patient (e.g., a human) orally. Insome embodiments, the free base crystalline form of Compound 1 describedherein is administered to a patient (e.g., a human) intravenously,intramuscularly, or via subcutaneous or intrasternal injection. Theeffective amount may be an amount sufficient to modulate C5a receptoractivity and/or an amount sufficient to reduce or alleviate the symptomspresented by the patient. Preferably, the amount administered issufficient to yield a plasma concentration of the compound (or itsactive metabolite, if the compound is a pro-drug) high enough todetectably inhibit white blood cell (e.g., neutrophil) chemotaxis invitro.

For treatment of most disorders via oral administration, a person ofskill in the art may determine the appropriate frequency ofadministration. In some embodiments, a frequency of administration of 4times daily or less is preferred. In some embodiments, a dosage regimenof 2 times daily is used. In some embodiments, once daily administrationis used. The patient may be administered a free base crystalline form ofCompound 1 in a fed or fasted state. In some embodiments, the patienttakes the free base crystalline form Compound 1 with food. In someembodiments, the patient takes the free base crystalline form ofCompound 1 without food.

For treatment of most disorders via intravenous, intramuscularadministration or via subcutaneous or intrasternal injection, a personof skill in the art may determine the appropriate frequency ofadministration. In some embodiments, the frequency of administration isabout once every two weeks. In some embodiments, the frequency ofadministration is about once every week. In some embodiments, thefrequency of administration is about three times a week. In someembodiments, the frequency of administration is about 2 to 5 times aweek. In some embodiments, the frequency of administration is about onceevery other day. In some embodiments, the frequency of administration isabout once a day.

It will be understood, however, that the specific dose level andtreatment regimen for any particular patient will depend upon a varietyof factors including the the age, body weight, general health, sex,diet, time of administration, route of administration, rate ofexcretion, drug combination (i.e., other drugs being administered to thepatient) and the severity of the particular disease undergoing therapy,as well as the judgment of the prescribing medical practitioner. Ingeneral, the use of the minimum dose sufficient to provide effectivetherapy is preferred. Patients may generally be monitored fortherapeutic effectiveness using medical or veterinary criteria suitablefor the condition being treated or prevented.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orpreventions of conditions involving pathogenic C5a activity (about 0.5mg to about 7 g per human patient per day). The amount of the free basecrystalline form of Compound 1 that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Dosage unitforms will generally contain between from about 1 mg to about 500 mg ofthe free base crystalline form of Compound 1. When administered orally,transdermally, intravaneously, or subcutaneously, it is preferred thatsufficient amount of the free base crystalline form of Compound 1 beadministered to achieve a serum concentration of 5 ng (nanograms)/mL-10μg (micrograms)/mL serum, more preferably sufficient compound to achievea serum concentration of 20 ng-1 μg/ml serum should be administered,most preferably sufficient compound to achieve a serum concentration of50 ng/ml-200 ng/ml serum should be administered. For direct injectioninto the synovium (for the treatment of arthritis) sufficient amounts ofthe free base crystalline form of Compound 1 should be administered toachieve a local concentration of approximately 1 micromolar.

E. Combination Therapy

The presently disclosed methods may include combination therapy with oneor more additional therapeutic agents that are used in the treatment,prevention, suppression or amelioration of the diseases or conditionsinvolving pathologic activation of C5a receptors. Such one or moreadditional therapeutic agents may be administered, by a route and in anamount commonly used therefor, contemporaneously or sequentially withthe free base crystalline form of Compound 1. When the free basecrystalline form of Compound 1 is used contemporaneously with theadditional therapeutic agent, a pharmaceutical composition containingsuch other drugs in addition to the free base crystalline form ofCompound 1 is preferred. Accordingly, the pharmaceutical compositions ofthe present disclosure include those that also contain one or more otheractive ingredients or therapeutic agents, in addition to the free basecrystalline form of Compound 1.

Examples of the one or more additional therapeutic agents arecorticosteroids, steroids, immunosuppressants, Immunoglobulin Gagonists, Dipeptidyl peptidase IV inhibitors, Lymphocyte functionantigen-3 receptor antagonists, Interleukin-2 ligands, Interleukin-1beta ligand inhibitors, IL-2 receptor alpha subunit inhibitors, HGF genestimulators, IL-6 antagonists, IL-5 antagonists, Alpha 1 antitrypsinstimulators, Cannabinoid receptor antagonists, Histone deacetylaseinhibitors, AKT protein kinase inhibitors, CD20 inhibitors, Abl tyrosinekinase inhibitors, JAK tyrosine kinase inhibitors, TNF alpha ligandinhibitors, Hemoglobin modulators, TNF antagonists, proteasomeinhibitors, CD3 modulators, Hsp 70 family inhibitors, Immunoglobulinagonists, CD30 antagonists, tubulin antagonists, Sphingosine-1-phosphatereceptor-1 agonists, connective tissue growth factor ligand inhibitors,caspase inhibitors, adrenocorticotrophic hormone ligands, Btk tyrosinekinase inhibitors, Complement C1s subcomponent inhibitors,Erythropoietin receptor agonists, B-lymphocyte stimulator ligandinhibitors, Cyclin-dependent kinase-2 inhibitors, P-selectinglycoprotein ligand-1 stimulators, mTOR inhibitors, Elongation factor 2inhibitors, Cell adhesion molecule inhibitors, Factor XIII agonists,Calcineurin inhibitors, Immunoglobulin G1 agonists, Inosinemonophosphate dehydrogenase inhibitors, Complement C1s subcomponentinhibitors, Thymidine kinase modulators, Cytotoxic T-lymphocyteprotein-4 modulators, Angiotensin II receptor antagonists, AngiotensinII receptor modulators, TNF superfamily receptor 12A antagonists, CD52antagonists, Adenosine deaminase inhibitors, T-cell differentiationantigen CD6 inhibitors, FGF-7 ligands, dihydroorotate dehydrogenaseinhibitors, Syk tyrosine kinase inhibitors, Interferon type I receptorantagonists, Interferon alpha ligand inhibitors, Macrophage migrationinhibitory factor inhibitors, Integrin alpha-V/beta-6 antagonists,Cysteine protease stimulators, p38 MAP kinase inhibitors, TP53 geneinhibitors, Shiga like toxin I inhibitors, Fucosyltransferase 6stimulators, Interleukin 22 ligands, IRS1 gene inhibitors, Proteinkinase C stimulators, Protein kinase C alpha inhibitors, CD74antagonists, Immunoglobulin gamma Fc receptor IIB antagonists, T-cellantigen CD7 inhibitors, CD95 antagonists, N acetylmannosamine kinasestimulators, Cardiotrophin-1 ligands, Leukocyte elastase inhibitors,CD40 ligand receptor antagonists, CD40 ligand modulators, IL-17antagonists, TLR-2 antagonists, Mannan-binding lectin serine protease-2(MASP-2) inhibitors, Factor B inhibitors, Factor D inhibitors, C3aRmodulators, C5aR2 modulators, T cell receptor antagonists, PD-1inhibitors, PD-L1 inhibitors, TIGIT inhibitors, TIM-3 inhibitors, LAG-3inhibitors, VISTA inhibitors, STING agonists, IDO inhibitors, adenosinereceptor modulators, CD39 inhibitors, CD73 inhibitors, antagonists ofthe chemokine receptors, especially CXCR1, CXCR2, CXCR3, CXCR4, CXCR7,CCR1, CCR2, CCR3, CCR4, CCR5, CCR7, CCR7, CCR9, CX3CR1 and CXCR6, andcombinations thereof.

In some embodiments, the additional therapeutic agent used in thetherapeutic methods herein, is selected from the group consisting ofobinutuzumab, rituximab, ocrelizumab, tositumomab, obinutuzumab,ibritumomab, cyclophosphamide, prednisone, hydrocortisone,hydrocortisone acetate, cortisone acetate, tixocortol pivalate,prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolonealcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide,fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodiumphosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone,hydrocortisone-17-valerate, halometasone, alclometasone dipropionate,beclomethasone, betamethasone valerate, betamethasone dipropionate,prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate,fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate,hydrocortisone-17-butyrate, hydrocortisone-17-aceponate,hydrocortisone-17-buteprate, ciclesonide and prednicarbate, GB-0998,immuglo, begelomab, alefacept, aldesleukin, gevokizumab, daclizumab,basiliximab, inolimomab, beperminogene perplasmid, sirukumab,tocilizumab, clazakizumab, mepolizumab, fingolimod, panobinostat,triciribine, nilotinib, imatinib, tofacitinib, momelotinib, peficitinib,itacitinib, infliximab, PEG-bHb-CO, etanercept, ixazomib, bortezomib,muromonab, otelixizumab, gusperimus, brentuximab vedotin, Ponesimod,KRP-203, FG-3019, emricasan, corticotropin, ibrutinib, cinryze,conestat, methoxy polyethylene glycol-epoetin beta, belimumab,blisibimod, atacicept, seliciclib, neihulizumab, everolimus, sirolimus,denileukin diftitox, LMB-2, natalizumab, catridecacog, ciclosporin,tacrolimus, voclosporin, voclosporin, canakinumab, mycophenolate,mizoribine, CE-1145, TK-DLI, abatacept, belatacept, olmesartanmedoxomil, sparsentan, TXA-127, BIIB-023, alemtuzumab, pentostatin,itolizumab, palifermin, leflunomide, PRO-140, cenicriviroc,fostamatinib, anifrolumab, sifalimumab, BAX-069, BG-00011, losmapimod,QPI-1002, ShigamAbs, TZ-101, F-652, reparixin, ladarixin, PTX-9908,aganirsen, APH-703, sotrastaurin, sotrastaurin, milatuzumab, SM-101,T-Guard, APG-101, DEX-M74, cardiotrophin-1, tiprelestat, ASKP-1240,BMS-986004, HPH-116, KD-025, OPN-305, TOL-101, defibrotide,pomalidomide, Thymoglobulin, laquinimod, remestemcel-L, Equineantithymocyte immunoglobulin, Stempeucel, LIV-Gamma, Octagam 10%,t2c-001, 99mTc-sestamibi, Clairyg, Prosorba, pomalidomide, laquinimod,teplizumab, FCRx, solnatide, foralumab, ATIR-101, BPX-501, ACP-01,ALLO-ASC-DFU, irbesartan+propagermanium, ApoCell, cannabidiol, RGI-2001,saratin, anti-CD3 bivalent antibody-diphtheria toxin conjugate, NOX-100,LT-1951, OMS721, ALN-CCS, ACH-4471, AMY-101, Acthar gel, and CD4+CD25+regulatory T-cells, MEDI7814, P32, P59, pembrolizumab, nivolumab,atezolizumab, avelumab, durvalumab, CCX354, CCX721, CCX9588, CCX140,CCX872, CCX598, CCX6239, CCX587, CCX624, CCX282, CCX025, CCX507, CCX430,CCX765, CCX758, CCX771, CCX662, CCX650, and combinations thereof.

IV. Examples

The following examples are provided to help illustrate the describedinvention and are not intended to limit the scope of what the inventorsregard as their invention.

Example 1: Preparing a Crystalline Form of Compound 1

Crude Compound 1 was prepared essentially as described in WO2016/053890.

A crystalline form of Compound 1 was prepared by dissolving 18 g ofcrude Compound 1 in 50 mL acetone with heating at 40° C. (aconcentration of about −0.0.36 g/mL). The warm solution was passedthrough a 10 μm polyethylene filter. The solution was then loaded intorotary evaporator at 30° C. bath temperature and 180 rpm rotationalspeed. The solid collected was dried further in a 45° C. oven for 1hour. The XRPD data of the crystalline form is shown in FIG. 1 , and thetable of peaks measured are listed in Table 1, below.

TABLE 1 Significant Peaks of Free Base Crystalline Form of Compound 1Significant Peaks 2-theta (deg) 8.06 20.28 8.40 21.32 8.88 22.36 10.2022.60 10.72 23.14 12.35 23.46 13.44 24.42 14.10 24.66 15.21 25.05 16.0525.48 16.20 26.20 16.92 26.44 17.28 27.18 17.64 27.60 18.58 28.70 19.0029.28 19.44 29.60

Example 2: Differential Scanning Calorimetry (DSC) and ThermalGravimetic Analysis (TGA) of the Free Base Crystalline Form of Compound1

To evaluate the physical characteristics of the free base crystallineform of Compound 1, differential scanning calorimetry data wascollected. Differential scanning calorimeter model DSC25 from TAInstruments˜Waters LLC was used. Sample was weighed into a standardaluminum pan and sealed by a standard aluminum lid with pinhole. Themeasurement was completed by using 10° C./min scanning rate, under anitrogen purge. The DSC analysis determined that the free basecrystalline form exhibits a melting (on set) of ˜213° C. and aendothermic peak at around 216° C. A plot of the DSC thermogram is shownin FIG. 2 .

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference. Where a conflictexists between the instant application and a reference provided herein,the instant application shall dominate.

1. A pharmaceutical composition for oral use prepared using a free basecrystalline form of Compound 1

which is substantially free of other forms of Compound
 1. 2. Thepharmaceutical composition of claim 1, characterized by an X-ray powderdiffraction (XRPD) pattern comprising peaks at 8.1, 8.4, 14.1, 16.9, and19.0 degrees 2θ (±0.2 degrees 2θ).
 3. The pharmaceutical composition ofclaim 2, further characterized by XRPD peaks at 12.4, 15.2, 16.1, 24.4,and 24.7 degrees 2θ (±0.2 degrees 2θ)
 4. The pharmaceutical compositionof claim 1, characterized by an X-ray powder diffraction patternsubstantially in accordance with FIG. 1 .
 5. The pharmaceuticalcomposition of claim 1, further characterized by a differential scanningcalorimetry thermogram (DSC) comprising an endothermic peak at around216° C.
 6. The pharmaceutical composition of claim 1, furthercharacterized by a melting point onset of about 213° C. as determined bydifferential scanning calorimetry thermogram (DSC).
 7. Thepharmaceutical composition of claim 1, further characterized by a DSCsubstantially in accordance with FIG. 2 . 8.-28. (canceled)